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Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase
|Authors:||Sánchez-Murcia, Pedro A. ; Ruiz-Santaquiteria, Marta ; Toro, Miguel A.; Lucio, H. de; Jiménez, M. Angeles ; Gago, Federico ; Jiménez-Ruiz, Antonio; Camarasa Rius, María José ; Velázquez, Sonsoles|
|Publisher:||Royal Society of Chemistry (Great Britain)|
|Citation:||RSC Advances 5: 55784-55794 (2015)|
|Abstract:||All-hydrocarbon and lactam-bridged staples linking amino acid side-chains have been used to stabilize the α-helical motif in short 13-mer peptides that target critical protein-protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR). The design of the best positions for covalent hydrocarbon closure relied on a theoretical prediction of the degree of helicity of the corresponding cyclic peptides in water. Selected (i, i + 4) and (i, i + 7) hydrocarbon-stapled peptides were prepared by using solid-phase synthesis protocols and optimized ring-closing metathesis reactions under microwave conditions. Structural analysis by NMR spectroscopy confirmed high helical contents in aqueous TFE solutions for both types of helix-constrained cyclic peptides. Remarkably, the ability to prevent Li-TryR dimerization was reduced in both (i, i + 4) and (i, i + 7) hydrocarbon stapled peptides but was retained in the corresponding (i, i + 4) Glu-Lys lactam-bridged analogue, which also showed a higher resistance to proteolytic degradation by proteinase K relative to the linear peptide prototype. In silico studies indicated that the introduction of a hydrocarbon staple vs. a lactam bridge likely perturbs critical interactions required for proper binding of the peptide to the Li-TryR monomer.|
|Publisher version (URL):||http://dx.doi.org/10.1039/c5ra06853c|
|Appears in Collections:||(IQM) Artículos|
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